In the continuing search for new chemical moieties that can effectively modulate a variety of biological processes, the standard method for conducting a search is to screen a variety of pre-existing chemical moieties, for example, naturally occurring compounds or compounds which exist in synthetic libraries or databanks. The biological activity of the pre-existing chemical moieties is determined by applying the moieties to an assay which has been designed to test a particular property of the chemical moiety being screened, for example, a receptor binding assay which tests the ability of the moiety to bind to a particular receptor site.
In an effort to reduce the time and expense involved in screening a large number of randomly chosen compounds for biological activity, several developments have been made to provide libraries of compounds for the discovery of lead compounds. The chemical generation of molecular diversity has become a major tool in the search for novel lead structures. Currently, the known methods for chemically generating large numbers of molecularly diverse compounds generally involve the use of solid phase synthesis, in particular to synthesize and identify peptides and peptide libraries. See, for example, Lebl et al., Int. J. Pept. Prot. Res., 41, p. 201 (1993) which discloses methodologies providing selectively cleavable linkers between peptide and resin such that a certain amount of peptide can be liberated from the resin and assayed in soluble form while some of the peptide still remains attached to the resin, where it can be sequenced; Lam et al., Nature, 354, p. 82 (1991) and (WO 92/00091) which disclose a method of synthesis of linear peptides on a solid support such as polystyrene or polyacrylamide resin; Geysen et al., J. Immunol. Meth., 102, p. 259 (1987) which discloses the synthesis of peptides on derivatized polystyrene pins which are arranged on a block in such a way that they correspond to the arrangement of wells in a 96-well microtiter plate; and Houghten et al., Nature, 354, p. 84 (1991) and WO 92/09300 which disclose an approach to de novo determination of antibody or receptor binding sequences involving soluble peptide pools.
The major drawback, aside from technical considerations, with all of these methods for lead generation is the quality of the lead. Linear peptides historically have represented relatively poor leads for pharmaceutical design. In particular, there is no rational strategy for conversion of a linear peptide into a non-peptide lead. As noted above, one must resort to screening large databanks of compounds, with each compound being tested individually, in order to determine non-peptide leads for peptide receptors.
In this respect, there has been increasing interest in the application of solid phase synthesis to the preparation of organic compounds, especially in the context of combinatorial chemistry and multiple simultaneous synthesis. One of the limitations in the solid phase approach involves the linker by which the organic molecule is attached to the solid support. Most linkers are based on protecting group chemistry and require the presence of an appropriate functional group in the target molecules being synthesized. Recently Plunkett and Ellman, J. Org. Chem. 1995, 60, 6006-6007 and Chenera et al., J. Amer. Chem. Soc. 1995, in press (see also, WO 95/16712 published Jun. 22, 1995), have described resin-bound aryl silane intermediates (1 and 2 shown below, wherein PS represents the polystyrene matrix and R represents the rest of the organic molecule synthesized on the resin) in which the aryl silane bond is cleaved by strong acid or fluoride ion to release the unfunctionalized aryl moiety. ##STR1##
A modified version (see dotted box of resin-bound aryl silane intermediate 3, above) of Chenera linker 2 was used in preparing an election deficient aromatic carbocycle as shown in Scheme 1 (Compound 4-Scheme 1). However, by using modified linker 3, an unexpected alternate synthetic route was taken and the desired election deficient aromatic carbocycle 4-Scheme 1 was not recovered after neat TFA cleavage from the resin. Since the use of neat TFA for cleaving aromatic carbocycles from a resin-bound aryl silane intermediate presents several synthetic advantages, the need for a silane linker useful in solid phase synthesis for preparing election deficient aromatic carbocyles which can be cleaved from a polymeric resin by neat TFA was demonstrated. As a result, the improved aryl silane linker described herein was designed.